EP3270018A1 - Mikrofluidische flusssteuerung und -vorrichtung - Google Patents

Mikrofluidische flusssteuerung und -vorrichtung Download PDF

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Publication number
EP3270018A1
EP3270018A1 EP17164473.5A EP17164473A EP3270018A1 EP 3270018 A1 EP3270018 A1 EP 3270018A1 EP 17164473 A EP17164473 A EP 17164473A EP 3270018 A1 EP3270018 A1 EP 3270018A1
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EP
European Patent Office
Prior art keywords
channel
substrate
fluid
flexible
flexible layer
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Pending
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EP17164473.5A
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English (en)
French (fr)
Inventor
Wolfgang Reiter
Alfred Paris
Daniel Horner
Thomas UMUNDUM
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Stratec Consumables GmbH
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Stratec Consumables GmbH
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Publication of EP3270018A1 publication Critical patent/EP3270018A1/de
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502738—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by integrated valves
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502707—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the manufacture of the container or its components
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B32—LAYERED PRODUCTS
    • B32B—LAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM
    • B32B37/00—Methods or apparatus for laminating, e.g. by curing or by ultrasonic bonding
    • B32B37/06—Methods or apparatus for laminating, e.g. by curing or by ultrasonic bonding characterised by the heating method
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B32—LAYERED PRODUCTS
    • B32B—LAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM
    • B32B37/00—Methods or apparatus for laminating, e.g. by curing or by ultrasonic bonding
    • B32B37/10—Methods or apparatus for laminating, e.g. by curing or by ultrasonic bonding characterised by the pressing technique, e.g. using action of vacuum or fluid pressure
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B32—LAYERED PRODUCTS
    • B32B—LAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM
    • B32B37/00—Methods or apparatus for laminating, e.g. by curing or by ultrasonic bonding
    • B32B37/12—Methods or apparatus for laminating, e.g. by curing or by ultrasonic bonding characterised by using adhesives
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B32—LAYERED PRODUCTS
    • B32B—LAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM
    • B32B38/00—Ancillary operations in connection with laminating processes
    • B32B38/0008—Electrical discharge treatment, e.g. corona, plasma treatment; wave energy or particle radiation
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K99/00—Subject matter not provided for in other groups of this subclass
    • F16K99/0001—Microvalves
    • F16K99/0003—Constructional types of microvalves; Details of the cutting-off member
    • F16K99/0015—Diaphragm or membrane valves
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K99/00—Subject matter not provided for in other groups of this subclass
    • F16K99/0001—Microvalves
    • F16K99/0003—Constructional types of microvalves; Details of the cutting-off member
    • F16K99/0026—Valves using channel deformation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0874—Three dimensional network
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0887—Laminated structure
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/12—Specific details about materials
    • B01L2300/123—Flexible; Elastomeric
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/06—Valves, specific forms thereof
    • B01L2400/0633—Valves, specific forms thereof with moving parts
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/06—Valves, specific forms thereof
    • B01L2400/0633—Valves, specific forms thereof with moving parts
    • B01L2400/0655—Valves, specific forms thereof with moving parts pinch valves
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L9/00—Supporting devices; Holding devices
    • B01L9/52—Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips
    • B01L9/527—Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips for microfluidic devices, e.g. used for lab-on-a-chip
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K99/00—Subject matter not provided for in other groups of this subclass
    • F16K2099/0073—Fabrication methods specifically adapted for microvalves
    • F16K2099/008—Multi-layer fabrications

Definitions

  • This disclosure relates to microfluidic flow control and to microfluidic devices.
  • Microfluidic devices are used for fluid manipulation at a small scale, typically characterised by fluid volumes measured in pL (microlitres).
  • fluids are manipulated within microfluidic channels or other formations, typically being formations provided in a structure of one or more layers by an etching, moulding, laser cutting, milling, hot embossing or lithographic process.
  • a microfluidic flow controller comprising a substrate having formations defining two or more substrate fluid channels having channel fluid ports which are open at an outer surface of the substrate; and a flexible layer having formations defining a flexible fluid channel which, when the flexible layer is positioned over the substrate so as to cover at least the channel fluid ports, provides a fluid communication path between the channel fluid ports but which, when a force is applied to press the flexible layer towards the substrate, deforms so as to inhibit fluid communication between the channel fluid ports.
  • Figures 1 and 2 are schematic diagrams illustrating the operation of a microfluidic flow controller.
  • the flow controller in Figures 1 and 2 is shown in cross-section (the upper left portion of each of the two drawings), cross-sectional side elevation (the upper right portion of each of the drawings) and a partial cross-sectional plan view (lower portion of each of the drawings).
  • the three representations in each drawing are laterally aligned with one another.
  • a microfluidic flow controller (for example, a valve) 100 is formed by a portion of a substrate 110 and a flexible layer 120.
  • the substrate has formations defining two or more substrate fluid channels 130, 140 having channel ends 150, 160 which are open at an upper surface (as drawn) of the substrate.
  • This provides an example of a microfluidic flow controller in which at least one of the channels is open to the substrate surface, and an example of a microfluidic flow controller in which at least one channel fluid port is an end of the respective channel.
  • the channels may have a width and/or depth of (for example) 10 ⁇ m to 1mm.
  • the flexible layer 120 has formations defining a flexible fluid channel 170. It may be, for example, bonded to the substrate.
  • An example arrangement has a flexible fluid channel with a cross-sectional area of 0.024mm 2 , a channel length of 1.35mm and a total internal volume of just 30 nanolitres. More generally, a cross-sectional dimension of the flexible fluid channel is selected from the list consisting of: (i) less than 1mm; (ii) less than 500 ⁇ m; (iii) less than 200 ⁇ m; and (iv) less than 50 ⁇ m. Such small dimensions can help to provide a small dead volume.
  • An example cross section of a flexible fluid channel will be described below with reference to Figure 9 .
  • Figure 1 shows the micro fluidic flow controller in an "open” configuration so that fluid may flow between the channels 130 and 140
  • Figure 2 shows the microfluidic flow controller in a "closed” configuration so that fluid flow is inhibited between the channels 130, 140.
  • the substrate 110 is a generally rigid material such as a plastics or glass type of material in which microfluidic formations including the channels under discussion are provided by an etching, stamping, embossing or other process. Specific examples of suitable materials will be discussed in detail below.
  • the flexible layer 120 is formed of a flexible material such as an elastomeric material which can, at least to an extent, deform under application of external force. Specific examples of suitable materials will be discussed in detail below.
  • the flexible layer could be, for example, injection moulded.
  • the flexible layer can be used as follows.
  • the flexible fluid channel 170 is positioned over the substrate so as to cover at least the channel ends 150, 160, which are examples of channel fluid ports. Other examples of channel fluid ports will be discussed below.
  • the flexible fluid channel 170 provides a fluid communication path between the channels ends but, when a force is applied to press the flexible layer towards the substrate, the flexible fluid channel deforms so as to inhibit fluid communication between the channel ends.
  • the flexible layer provides a cover for at least some of the remaining portions of the channels 130, 140.
  • the flow controller is "open" and fluid may flow along one of the channels and through its channel end into the flexible fluid channel 170 and from there, passing through the channel end of the other of the channels along the second channel.
  • the flexible fluid channel provides a fluid flow path in this configuration. This can be seen in the lower (plan view) cross-sectional drawing of Figure 1 , where it is noted that the example fluid flow from left to right is merely for the purposes of illustration; fluid flow could be in either direction.
  • a mechanical force shown schematically by an arrow 180 is applied to the flexible layer so as to deform the flexible fluid channel 170 such that fluid flow between the channels 130, 140 is inhibited.
  • the fluid flow is substantially (or indeed, in some examples, completely) stopped. It will be appreciated that in other examples the operation of the microfluidic flow controller does not have to be a binary "on/off control but instead the amount of restriction in the fluid path from the channel 130 to the channel 140 could be varied between fully on and fully off.
  • the flexible fluid channel 170 is formed, for example, as one or more indentations or recesses (such as an elongate recess of the type shown in the present drawings) in the flexible layer itself, and the flexible layer is deformed by the application of the external force 180. So, when the flow controller is "open" fluid flow is diverted along the channel formed by the one or more indentations or recesses in the flexible layer 120. Fluid flow is inhibited by deforming the flexible layer so as to close (or at least partially close) the flexible fluid channel 170 formed within the flexible layer 120.
  • the flexible fluid channel is (from the point of view of the flexible layer) an open channel so that for at least part of the fluid flow path through the flexible fluid channel, one or more sides of the flexible fluid channel are provided by the surface of the substrate (such as a part of the surface between the channel fluid ports).
  • the flexible fluid channel could be a closed channel enclosed within the flexible layer.
  • more than one side of the flexible fluid channel could be provided by substrate (for example, rigid) formations.
  • at least a part of one or more sides of the flexible fluid channel could be provided by formations upstanding from the substrate surface.
  • the fluid follows a path from the channel 130 to the channel 140 involving multiple right angle turns.
  • these right angle turns may in part, in example arrangements one or both of: (i) the ends of the flexible fluid channel 170; and (ii) the channel ends 150, 160 are chamfered.
  • the term chamfering encompasses any shaping which tends to round off, smooth or otherwise lessen the abrupt right angle turns shown in Figure 1 .
  • the ends of the flexible fluid channel and/or the channel ends themselves could be angled (as shown schematically in Figure 3b , in comparison with the right angles in Figure 3a ) so as to provide a diversion of the fluid flow (to pass through the flexible fluid channel 170) of less than 90 degrees.
  • the flexible layer (or a part of it) is shown as item 300, 300'.
  • Substrate channel ends 310, 310' connect to a flexible fluid channel 320, 320'.
  • the ends could be radiused or otherwise shaped so as to reduce the abrupt nature of the diversion of the fluid flow.
  • Figures 4 and 5 schematically illustrate a flexible layer 400, shown in various views which are: plan view from above (upper left of Figure 4 ), side elevation ( Figure 4 , upper right), cross-sectional side view ( Figure 4 , lower portion) and plan view from below ( Figure 5 ).
  • these various views show the flexible fluid channel 170 and one or more control formations 420.
  • the control formations are positioned with respect to the flexible fluid channel so that when a force is applied to the one or more control formations, the flexible fluid channel is deformed as discussed above.
  • the one or more control formations are configured so that application of an external force to an activation area of the one or more control formations causes deformation of the flexible fluid channel, the activation area being wider than the width of the flexible fluid channel.
  • the activation area is basically anywhere on either of the lobes 422 or the central area 424 of the formation 420, so that the activation area has a width 430 which is wider than the width 440 of the flexible fluid channel 170.
  • This greater width of the activation area allows for a partial relaxation of the positioning requirements of, for example, an external actuator used to provide the external force to close the flexible fluid channel (noting that the channel will tend to reopen upon removal of the external force because of its elastic behaviour, or in other words that the flow controller of these examples is a normally open flow controller).
  • an external actuator used to provide the external force to close the flexible fluid channel (noting that the channel will tend to reopen upon removal of the external force because of its elastic behaviour, or in other words that the flow controller of these examples is a normally open flow controller).
  • This in turn can mean that cheaper or more tolerant assembly and/or components may be used in, for example, a microfluidic system including a device having one or more flow controllers of the type being described here.
  • the twin lobed arrangement of the control formations 420 can provide efficient operation in that if an external actuator presses on the two lobes, they will tend to collapse the channel by directing the pushing force from two sides towards the channel, thereby potentially reducing the required force and allowing cheaper or less powerful or less power-consuming actuators to be used.
  • the shape of the control formations provides that the force applied to the control formations will tend to be directed towards deforming the flexible fluid channel disposed (in this example) centrally between the two lobes. Reference is made to the arrows in the side elevation of Figure 4 .
  • control formations may be moulded or otherwise fabricated with the rest of the flexible layer, or may be fixed to it later (for example, glued). They may be formed of the same material as the flexible layer or may be formed of another material, for example a more rigid material than that used in the flexible layer.
  • Figures 6 and 7 provide isometric (perspective) views of the flexible layer 400 of Figures 4 and 5 .
  • Figure 6 is an isometric upper view (where "upper” refers to a surface of the flexible layer 400 which does not contact the substrate 110) and
  • Figure 7 shows an isometric "lower” view of the same flexible layer 400, as seen in the direction A shown in Figure 6 .
  • FIGs 8a to 8f schematically illustrate alternative examples of control formations.
  • the control formations are shown on their own in Figures 8a to 8f , and in Figures 8a-1 to 8f-1 respectively they are shown when part of a flexible layer (either through being formed as part of the flexible layer or by being fabricated separately and fixed to the flexible layer, for example by gluing, welding or other process).
  • the control formations protrude from the upper (non-substrate-contacting) surface of the flexible layer in a similar manner to those shown in Figure 4 .
  • the control formations provide an activation area (such as the upper face of the control formations) which has a width greater than the width of the flexible fluid channel.
  • other control formations not complying with this constraint could be used.
  • the actuator/pusher When the actuator/pusher hits the activation structure, it will be pressed into the elastomeric or flexible layer. As the activation structure is positioned exactly above the channel, the force is introduced at the right position to collapse the channel.
  • a useful shape of the activation structure depends on multiple parameters such as elasticity of the material for the elastomeric layer, thickness of the elastomeric layer and cross section of the microfluidic channel.
  • a flow controller may work without the need of an activation structure.
  • a simple pillar shape round, rectangular of square
  • the actuation timing time to fully close or allow to reopen the channel
  • Empirical tests have shown that a more complicated actuator shape (as shown in the drawings) gave improved performance compared to a simple pillar shape.
  • actuation of the flow controller can be done by a mechanical pusher, which can be manually or automated operated. Any linear motion with adequate stroke (about same as total thickness of the elastomeric layer) may be applied. To aim towards reliable and efficient operation, there could be any appropriate mechanical shape of the elastomeric part and the pusher.
  • Such activation structure can be part of the elastomeric layer or part of the actuator. If it is part of the actuator, it needs to be positioned so as to be generally centred above the microfluidic channel.
  • the positioning of the actuator is not critical.
  • a flat surface of the actuator cap may hit the full top area of the activation structure.
  • an offset of+/-0,5mm is allowed.
  • the activation structure can be an integrated part of the elastomeric layer (monolithic) or can be mounted on top of the elastomeric layer (for example glued).
  • Figure 9 schematically illustrates a cross section of a flexible fluid channel.
  • the flexible fluid channel shape is designed to meet following main criteria: (a) required flow rate (direct relation to orifice); (b) allowable dead volumes (should be usually as small as possible for microfluidics); (c) to enable collapsing and sealing of the channel with low force; and/or (d) to enable quick and reliable full self-recovery of the channel after actuation.
  • a 45° draft angle of the flexible fluid channel side walls, as well as a height to base width ratio of 1:3.5 has been tested empirically as a useful configuration for collapsing and sealing of the channel with low force on the one hand and quick and reliable self-opening on the other hand.
  • the geometries of the elastomeric layer may be tuned to the dedicated channel size and the properties of the elastomer to ensure adequate functionality.
  • the size of the elastomeric layer (or at least that portion containing the flexible fluid channel) can be basically any shape, but may depend on criteria such as (a) channel dimension (length, width, ...); (b) to enable sufficient area for sealing (to allow proper bonding); (c) optionally to act as a cover layer for the channels of the microfluidic component; and/or (d) whether clustering of flow controllers is required
  • the thickness of the elastomeric layer may depend on criteria such as: (a) channel height; (b) hardness of the elastomeric material; and/or (c) required switching performance (on/off-timing).
  • a ratio of channel height to body height of 1:7 has been demonstrated for good functionality for the material PDMS.
  • a ratio of 1 :>7 will increase closing force, a ratio of 1 : ⁇ 7 may slow opening speed and the ability for full recovery of channel cross section.
  • the flexible fluid channel volume is just defined by the flexible fluid channel cross section and the flexible fluid channel length.
  • valve valve
  • flow controller with a cross sectional area of 0,024mm 2 .
  • the flow controller just contains a total internal of 30nl.
  • the internal volumes of commercial currently available microfluidic valves or flow controllers usually start at (for example) 1ml, which is 30x more.
  • Performance data of a prototype flow controller with 350 ⁇ m wide and 100 ⁇ m high flexible fluid channel are as follows: (a) Flow rate: 14.267 ⁇ l/h (at a pressure caused by a height difference of just 200mm from inlet to outlet) based on: 75mm flow distance in a tube with 0.58mm inside diameter within 5 seconds; (b) approximate leakage rate at a fluid pressure of 2 bar was 15.852 ⁇ l/h based on: 1mm flow distance within 1min (at a cylinder pressure of 5 bar); (c) in a long term stability test, the flexible fluid channel reopened normally after 43h of closing (air pressure to cylinder: 5 bar); and (d) in a long run test, there was no visible change in functionality after 37,800 on/off cycles based on keeping the flow controller under Is on/off cycles for 21 hours.
  • Figure 10 is a schematic plan view of a substrate 1000 having substrate channels 1010, 1020 with channel ends 1030, 1040.
  • Figure 11 is a schematic plan view of a flexible layer 1050 having substantially the same size as the surface of the substrate and having a flexible fluid channel formed as an elongate indentation in a face of the flexible layer 1050 which will abut the face of the substrate 1000 in which the channel ends 1030, 1040 are provided.
  • Features such as chamfering and control structures are not shown in these Figures 10-12 for clarity of the diagrams.
  • the flexible layer 1050 is positioned over and, in at least example embodiments, bonded to the substrate 1000 so that the flexible fluid channel provides (at least when an external force is not applied) a fluid communication path between the channel ends 1030, 1040.
  • Figures 13-15 provide a similar arrangement but in this example the flexible layer 1400 (having a flexible fluid channel 1410) has a smaller size than the surface of the substrate 1000.
  • the flexible layer 1400 is at least large enough to encompass the size of the flexible fluid channel 1410 but instead of covering the entirety (or substantially the entirety) of an active area of the substrate 1000, it forms a patch on the surface of the substrate 1000.
  • This arrangement is particularly suited to a microfluidic device in which the channels in the substrate are normally covered (which is to say, they are closed channels, below the surface of the substrate, at least in regions not covered by the flexible layer or patch.
  • the channels1310, 1320 can, for example, be linked to the surface by vias 1330, 1340 as drawn. Another example of the use of vias in this way is given in Figures 18 and 19 discussed below.
  • Figures 16 and 17 schematically illustrate the operation of a flow controller of the type discussed above.
  • a mechanical actuator 1600 is movable between a retracted position ( Figure 16 ) and a forwarded or deployed position ( Figure 17 ).
  • a flexible fluid channel 1610 in a flexible layer 1620 is deformed by the movement of the actuator into the forwarded position so as to allow or block the flow of fluid along channels 1630, 1640 (one of which may be an inlet channel and the other an outlet channel) in a substrate 1650 of the microfluidic flow controller.
  • FIG. 18 and 19 A similar arrangement is shown in Figures 18 and 19 .
  • a mechanical actuator 1800 is used.
  • An example flexible layer 1810 forms a patch rather than a complete layer covering the whole substrate, and the flexible fluid channel 1820 is formed in a surface of the flexible layer 1810 adjacent to an upper layer 1830 of the substrate.
  • Fluid channels 1840, 1850 are provided within the substrate (not at the surface of the substrate structure) and so-called vias 1860, 1870 are provided to link the channels 1840, 1850 to the upper surface 1830 of the substrate structure where they link with the flexible fluid channel for operation of the flow controller.
  • This provides an example of a microfluidic flow controller in which at least one of the channel fluid ports is the end of a via which connects that channel fluid port to a respective substrate fluid channel below a surface of the substrate.
  • Figure 20 is a schematic flow chart illustrating the fabrication of a flow controller and/or a microfluidic device.
  • a substrate or substrate structure is fabricated including microfluidic channels and possibly other microfluidic components or features. For example, an existing etching, stamping or embossing process can be used.
  • a flexible layer is fabricated, for example using injection moulding.
  • the surface of the substrate (to which the flexible layer will be bonded) is activated.
  • the bonding surface of the flexible layer can also be activated at a step 2025.
  • Examples of activation techniques include plasma activation, solvent activation, or activation by exposure to gas or ultraviolet light.
  • the substrate and flexible layer are aligned with one another (for example using alignment marks or formations on them and an optical alignment process).
  • the two parts are pressed together and this pressure is maintained while, at a step 2050, heat is applied.
  • the flexible layer is attached to the substrate by an attachment selected from the list consisting of: (i) bonding, (ii) welding, (iii) gluing and (iv) clamping.
  • Figure 20 therefore provides an example of a method of manufacturing a microfluidic flow controller, the method comprising fabricating a substrate having formations defining two or more substrate fluid channels having channel fluid ports which are open at an outer surface of the substrate; and positioning a flexible layer over the substrate, the flexible layer having formations defining a fluid channel so that, when the flexible layer is positioned over the substrate so as to cover at least the channel fluid ports, the flexible fluid channel provides a fluid communication path between the channel fluid ports but, when a force is applied to press the flexible layer towards the substrate, the flexible fluid channel deforms so as to inhibit fluid communication between the channel fluid ports.
  • the method may include fabricating the flexible layer by injection moulding.
  • the method may include bonding the flexible layer to the substrate.
  • the bonding step may comprise bonding the flexible layer to the substrate by plasma activated bonding.
  • FIGS 21-23 schematically illustrate a microfluidic system which may include a microfluidic device comprising one or more microfluidic flow controllers as discussed above.
  • a microfluidic device 2100 comprising a substrate 2120 covered with a flexible layer 2110 as discussed above (and possibly including various other microfluidic features) is mounted in a frame 2120 comprising, amongst other features, mechanical actuators 2130 to press down onto the flexible layer (for example, onto control structures on the flexible layer) to actuate the microfluidic flow controllers provided in the microfluidic device.
  • a controller such as a computer running appropriate computer software 2140 controls operation of the device and the flow controller actuators in particular.
  • a fluid input/output arrangement 2150 can be provided to control the flow of fluids under test into and out of the microfluidic device.
  • the frame 2120 and other features can be reused whereas the microfluidic device can be, for example, single-use so that when that use is finished, a new microfluidic device can be inserted into the frame and actuator arrangement.
  • Figure 22 shows the frame and actuators of the system of Figure 21 without the microfluidic device in place. As mentioned, this can be used multiple times with a new microfluidic device inserted into place each time (the controller and fluid input/output are not shown in Figure 22 or indeed in Figure 23 for clarity of the diagram).
  • the flexible layer 2300 including the flexible fluid channel 2310 can be provided as part of the reusable system rather than being provided as part of the microfluidic device, so that in use, a microfluidic device comprising a substrate having appropriately positioned channel formations and channel ends is placed into the frame 2120 of Figure 23 such that the channel ends are aligned with the flexible fluid channels 2310.
  • the flexible layer is provided as part of the reusable device, being bonded to the substrate or otherwise held to the substrate (for example, by clips or a frame) at manufacture. This reduces the need for such precise alignment and sealing of the flexible fluid channel to the substrate at the point of use.
  • Figures 21-23 therefore provide examples of a microfluidic system comprising: a support to receive a microfluidic device as discussed above; and one or more actuators configured with respect to the position which the microfluidic device would adopt when held by the support, to provide pressure to press the flexible layer of the microfluidic device towards the substrate of the microfluidic device so as to deform the flexible fluid channel defined by the flexible layer.
  • the system may include the microfluidic device.
  • the device may be a disposable / single use device.
  • the flexible fluid channel provides a fluid path between channel ends of the microfluidic channels in the substrate
  • the linkage can take place part way along or both of the channels so that the channel fluid port need not be at the end of a channel.
  • Figure 24a where two microfluidic channels in a substrate 2410, 2420 are controllably linked by a flexible fluid channel 2430 at a point which is not a channel end on one or both of the channels.
  • the channels can be open to the surface or can provide a via or port to the surface 2440 of the substrate ( Figure 24b).
  • Figure 24c schematically illustrates an arrangement whereby a channel 2450 below the surface of the substrate is linked to the surface (to form a channel fluid port) by a via 2460 as described earlier.
  • the channel 2450 is a blind T-shaped channel.
  • the flexible fluid channel can provide a controllable fluid communication linkage between more than two channels.
  • the flexible fluid channel can provide a linkage between a channel in the substrate and, for example, a waste or exhaust port.
  • Example suitable materials for use as the substrate and for use as the flexible layer are discussed below.
  • elastomeric material can be used, as long it fulfils all related requirements for the dedicated application.
  • examples include elastomer, silicone or natural or synthetic rubber.
  • the manufacturing process for the elastomeric layer could be casting (curing/hardening by time, temperature, light, ...), injection moulding (e.g. for TPEs) or reactive injection moulding (e.g. for polyurethanes).
  • thermoplastic elastomer such as thermoplastic polyolefine (TPO), thermoplastic vulcanisate (TPV), thermoplastic rubber (TPR), styrene based thermoplastic (TPS), amid based thermoplastic (TPA), ester based thermoplastic (TPC), urethane based thermoplastic (TPU), any kind of silicone such as ploymethylsiloxan or any kind of natural or synthetic rubber such as NBR, FKM, EPDM, SEBS or the like.
  • TPE thermoplastic elastomer
  • TPO thermoplastic polyolefine
  • TPV thermoplastic vulcanisate
  • TPR thermoplastic rubber
  • TPS styrene based thermoplastic
  • TPA amid based thermoplastic
  • TPC ester based thermoplastic
  • TPU urethane based thermoplastic
  • any kind of silicone such as ploymethylsiloxan or any kind of natural or synthetic rubber such as NBR, FKM, EPDM, SEBS or the like.
  • the substrate may be formed of, for example, one or more of: a polymeric material; a material selected from glass, quartz, silicon nitride, and silicon oxide, polyolefines, polyethers, polyesters, polyamides, polyimides, polyvinylchlorides, polyacrylates; including their modifications, derivatives and copolymers; more specifically (by way of example) one of the list containing acrylnitril-butadien-styrole (ABS), cyclo-olefin-polymers and copolymers (COC/COP),Polymethylene-methacrylate (PMMA), Polycarbonate (PC), Polystyrole (PS), Polypropylene (PP), Polyvinylchloride (PVC), Polyamide (PA), Polyethylene (PE), Polyethylene-terephthalate (PET), Polytetrafluor-ethylene (PTFE), Polyoxymethylene (POM), Thermoplastic elastomers (TPE), thermoplastic polyurethane (TPU
  • Figures 25 and 26 are photographs of an example flow controller in use.
  • Figure 26 is a microscopic view of a device formed in transparent material, and shows two substrate channels 2600, two vias 2610 connecting the channels to the flexible fluid channel, and droplet flow between the vias 2620.
  • Example arrangements can provide an advantageously low dead volume and can, in at least some examples, keep the same channel cross section along the length of a valve or fluid flow controller. These features can help to alleviate the uncontrollable behaviour of fluids with dead volumes, the risk of releasing air bubbles from dead volumes and unintended changes in fluidic flow. Dead volume can be reduced or avoided because the flexible fluid channel is directly in the flow path and (in some examples) is smaller than the inlet and outlet channel fluid ports
  • a rigid substrate and a flexible layer providing some of the flow controlling functionality allow high precision parts of the microfluidic device to be formed in rigid material and only the actuating part of the flow controller in the flexible material which may be less difficult to mould, demould and shape.

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CA3096855A1 (en) 2018-05-23 2019-11-28 Miroculus Inc. Control of evaporation in digital microfluidics
CA3133124A1 (en) 2019-04-08 2020-10-15 Miroculus Inc. Multi-cartridge digital microfluidics apparatuses and methods of use
CN111044740B (zh) * 2019-12-02 2024-07-12 江苏圣极基因科技有限公司 微流道结构、流体测试装置及流体进样测试系统
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